The objective of the proposed research is to investigate how genes, environment, and gene-environment interactions influence temporal changes in body mass index (BMI) at vulnerable periods of the life cycle. Little is known about how individual susceptibility to environmental contexts influences attained size and trajectories of body mass change. We will leverage Framingham Heart Study genome-wide association study (GWAS) data to investigate interactions between genetic variation and modifiable environmental factors in the determination of body mass in two NIH-funded longitudinal cohort studies with high obesity incidence: The National Longitudinal Study of Adolescent Health (Add Health), a nationally representative sample of adolescents attending US schools in 1994 with 12 years of follow-up, including 5,000 European Americans, 2,100 African Americans, 1,500 Hispanic Americans and 900 Asian Americans;and the Cebu Longitudinal Health and Nutrition Survey (CLHNS), a cohort of 1,800 reproductive aged women with 20 years of follow up, which we will use to augment the Asian sample and to compare results across different environments. Both datasets provide detailed longitudinal data at individual, household, and community levels and sufficient DNA for extensive genotyping. Single nucleotide polymorphisms (SNP) selection will be based on: 1) GWAS data from the Framingham Heart Study, SNPs with greatest evidence for association with BMI level and change;and 2) literature-based candidates. In the first stage of genotyping, we will select approximately 7,300 SNPs for association testing in a subsample of the Add Health European-American sample. In a second stage, we will genotype approximately 1,200 of the most strongly associated SNPs from stage 1 in the rest of the European, African, Hispanic, and Asian American Add Health subsamples and in the CLHNS sample. Environmental factors, behaviors and genes that predict BMI level and change will be identified in each cohort, and then gene by environment interactions will be assessed in statistical models predicting BMI over time. Our study will further the understanding of how the effects of genetic variation are modified by the environment, a critical step towards development of efficacious programs for the prevention and treatment of obesity and the reduction of disparities in obesity by race/ethnicity and socioeconomic status. PUBLIC HEALTH RELEVANCE: The objective of the proposed research is to investigate how genes, environment, and gene-environment interactions influence temporal changes in body mass index (BMI) at vulnerable periods of the life cycle. Our study will further the understanding of how the effects of genetic variation are modified by the environment, a critical step towards development of efficacious programs for the prevention and treatment of obesity and the reduction of disparities in obesity by race/ethnicity and socioeconomic status.